The objectives of this proposed research are to make creative contributions to the total synthesis of naturally occurring substances possessing clinically significant biological activity. The present grant will continue to address the development of new stereoselective reactions and the application of this methodology to the asymmetric synthesis of ionophore and macrolide antibiotics and antineoplastic agents. The methodological studies dealing with new reaction discovery will emphasize the development of new reactions for controlling the stereochemical course of chemical processes. In the present study we will continue to focus our attention on "directable" chemical processes. These studies will focus on the continued development of an iridium-catalyzed directable hydroboration process, the development of a directable Meerwein-Ponndorff-Verley reduction based on samarium diiodide, and the application of intramolecular variants of the Tishchenko reaction for long-range directed reductions of ketones. The targets for total synthesis will include the development of asymmetric syntheses of the antineoplastic agents bryostatin, calyculin, macbecin, and herbimycin, the ionophore antibiotic lonomycin, and the oligomycin macrolide rutamycin.